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. 2016 Mar 1;3(6):567–572. doi: 10.1002/mdc3.12337

Long‐term Thalamic Deep Brain Stimulation for Essential Tremor: Clinical Outcome and Stimulation Parameters

Pedro M Rodríguez Cruz 1, Antonio Vargas 1, Carlos Fernández‐Carballal 1, Jose Garbizu 1, Beatriz De La Casa‐Fages 1, Francisco Grandas 1,✉
PMCID: PMC6178759  PMID: 30363558

Abstract

Background

The reasons underlying the loss of efficacy of deep brain stimulation (DBS) of the thalamic nucleus ventralis intermedius (VIM‐DBS) over time in patients with essential tremor are not well understood.

Methods

Long‐term clinical outcome and stimulation parameters were evaluated in 14 patients with essential tremor who underwent VIM‐DBS. The mean ± standard deviation postoperative follow‐up was 7.7 ± 3.8 years. At each visit (every 3–6 months), tremor was assessed using the Fahn‐Tolosa‐Marin tremor rating scale (FTM‐TRS) and stimulation parameters were recorded (contacts, voltage, frequency, pulse width, and total electrical energy delivered by the internal generator [TEED 1sec]).

Results

The mean reduction in FTM‐TRS score was 73.4% at 6 months after VIM‐DBS surgery (P < 0.001) and 50.1% at the last visit (P < 0.001). The gradual worsening of FTM‐TRS scores over time fit a linear regression model (coefficient of determination [R2] = 0.887; P < 0.001). Stimulation adjustments to optimize tremor control required a statistically significant increase in voltage (P = 0.01), pulse width (P = 0.01), frequency (P = 0.02), and TEED 1sec (P = 0.008). TEED 1sec fit a third‐order polynomial curve model throughout the follow‐up period (R2 = 0.966; P < 0.001). The initial exponential increase (first 4 years of VIM‐DBS) was followed by a plateau and a further increase from the seventh year onward.

Conclusions

The current findings suggest that the waning effect of VIM‐DBS over time in patients with essential tremor may be the consequence of a combination of factors. Superimposed on the progression of the disease, tolerance can occur during the early years of stimulation.

Keywords: essential tremor, deep brain stimulation, long‐term efficacy, tolerance, disease progression

Essential tremor (ET) is one of the most common neurological disorders.1 ET is a slowly progressive disease with a variable clinical course and response to pharmacological treatment that can result in significant functional disability in some patients.2, 3, 4 Deep brain stimulation (DBS) of the thalamic nucleus ventralis intermedius (VIM‐DBS) is an effective surgical treatment for selected patients with drug‐refractory ET.5 However, loss of efficacy over time gives cause for concern.6, 7 Up to one‐third of patients experience a worsening of tremor over months to years, and many need VIM‐DBS to be reprogrammed with higher stimulation parameters to control tremor deterioration.4 A recent study suggested that the potential loss of benefit of VIM‐DBS should be discussed during patient counselling on the durability of the expected benefit.8

The underlying reasons for the decline in tremor control by VIM‐DBS are not well understood. Tolerance to stimulation7, 9 and disease progression10 have been proposed as the most likely causes. Other factors, such as suboptimal lead placement,11 gradual loss of the microthalamotomy effect,12 and the potentially increased impedance in brain tissue over time,12, 13 may also play a role. To elucidate the possible causes of the loss of benefits from VIM‐DBS in the control of ET, we evaluated long‐term clinical outcome and stimulation parameters, particularly total electrical energy delivered by the internal generator (TEED1sec),14 in a series of patients who had drug‐refractory ET treated with VIM‐DBS at a single center.

Patients and Methods

This retrospective review of prospectively collected data was approved by the local ethics committee. We included patients with disabling, drug‐refractory ET who underwent lead implantation and programming with either unilateral or bilateral VIM‐DBS at Hospital General Universitario Gregorio Marañón (Madrid, Spain) and were followed for at least 2 years after surgery. Target localization was supported by intraoperative microrecordings, the clinical effect of intraoperative electrical stimulation, and postoperative stereotactic magnetic resonance imaging. We excluded patients who had no benefit after initial programming and those who lost the initial benefit within 6 months despite extensive reprogramming sessions. The clinical characteristics recorded included age, sex, duration of ET until surgery, current medication, and medication before VIM‐DBS.

All patients were implanted with devices from Medtronic Inc. (Minneapolis, MN, USA), which induce constant voltage stimulation. The implantable pulse generator was usually turned on 1–3 weeks after implantation. During the first 2 or 3 months, the stimulation parameters were adjusted to obtain maximal control of tremor without side effects. Patients were followed at routinely scheduled visits every 3–6 months. Additional unscheduled visits were allowed if required, according to the patient's clinical situation.

ET was assessed using the Fahn‐Tolosa‐Marin tremor rating scale (FTM‐TRS)15 before surgery and at each follow‐up visit. This scale evaluates tremor (part A), hand function (part B), and activities of daily living (part C). Stimulation settings, including type of stimulation (active contacts, monopolar/bipolar) amplitude (V), pulse width (μsec), and frequency (Hz), were registered at each follow‐up visit, and an analysis of impedance (Ω) was performed to rule out possible open or short circuits. Stimulation settings were reprogrammed to optimize the control of tremor when deemed necessary. This process usually involved increases in stimulation amplitude of from 0.2 to 0.5 V, increases in pulse width of 30 μsec, or frequency increases to a maximum of 190 Hz. The TEED1sec by the internal pulse generator was calculated for each follow‐up visit using the following equation: TEED1sec(J) = ([voltage2 × frequency × pulse width]/impedance) × 1 second.14 Like in previous studies, an impedance of 1000 Ω was adopted to calculate TEED1sec.16

The statistical analysis was performed using the statistical package SPSS version 15.0 (SPSS Inc., Chicago, IL, USA). To assess TEED1sec and FTM‐TRS over time, fitting curves were constructed using regression analysis. The coefficient of determination (R2) was used to assess the fit of the regression line to the data collected. The Wilcoxon signed‐rank test was used to determine statistically significant changes over time in the FTM‐TRS scores and stimulation parameters. Spearman's rank correlation coefficient (ρ) was used to measure statistical dependence between stimulation parameters and FTM‐TRS scores. The results are presented as mean values ± standard deviation. A P value <0.05 was considered significant.

Results

In total, 14 patients (10 men) were included in the study. Two other patients were excluded because of poor initial benefit due to suboptimal placement of the electrodes.

Eleven patients underwent bilateral VIM‐DBS placement, and 3 received unilateral leads. The mean age ± standard deviation at implantation was 61 ± 2.5 years. The mean duration of symptoms before surgery was 25 ± 10.5 years. The mean duration of follow‐up after surgery was 92.6 ± 45.5 months. Medications for ET were discontinued completely after VIM‐DBS surgery in 10 patients (71.5%), usually within the first 6 months. The FTM‐TRS scores and subscores over time are shown in Figure 1. The mean reduction in the total FTM‐TRS score was 73.4% 6 months after implantation (baseline, 63.3 ± 9.9; 6‐month follow‐up, 16.8 ± 11.2; P < 0.01) and 50.1% at the last follow‐up visit (baseline, 63.29; last follow‐up, 31.6 ± 8.2; P < 0.01). Similar statistically significant reductions were obtained for all FTM‐TRS subscores during the follow‐up period (Fig. 1). Although tremor improved throughout the follow‐up period, we detected a steady, mild, progressive worsening of FTM‐TRS scores that began after the first year of VIM‐DBS and fit a linear regression model (R2 = 0.887; P < 0.001) (Figs. 2, 3)

Figure 1.

Figure 1

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Mean Fahn‐Tolosa‐Marin (FTM) tremor rating scale scores and subscores (FTM‐A, FTM‐B, and FTM‐C) before surgery, 6 months after surgery, and at the last follow‐up visit are illustrated. This scale includes evaluation of tremor (part A), hand function (part B), and activities of daily living (part C). Double asterisks indicate P < 0.01. The results are presented as mean values.

Figure 2.

Figure 2

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Progress of scores on the Fahn‐Tolosa‐Marin tremor rating scale (FTM‐TRS) after surgery is illustrated. A steady, mild, progressive worsening of FTM‐TRS scores was observed beginning the first year after thalamic nucleus ventralis intermedius deep brain stimulation (VIM‐DBS) implantation. The FTM‐TRS score increased significantly compared with scores at the assessment 6 months after surgery (an asterisk indicates P < 0.05). The results are presented as mean values ± standard deviation. The numbers in parentheses represent patients who were included in the follow‐up at each time interval.

Figure 3.

Figure 3

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Total scores on the Fahn‐Tolosa‐Marin tremor rating scale (FTM‐TRS) are illustrated for individual patients during the follow‐up period.

To maintain an appropriate clinical response, stimulation parameters were adjusted if necessary (see above) throughout the follow‐up period (Table 1). At the last visit, significant increases were detected in voltage (2.1 ± 0.6 V at 6 months after surgery; 3.5 ± 0.6 V at the final visit; P = 0.01), pulse width (66.0 ± 19.4 μsec at 6 months after surgery; 90.0 ± 15.0 μsec at the final visit; P = 0.01), and frequency (130 ± 1.0 Hz at 6 months after surgery; 142.0 ± 10.0 Hz at the final visit; P = 0.02). TEED1sec increased significantly over time (43.1 ± 29.8 joules at 6 months after surgery, and 163.5 ± 62.1 joules at the final visit; P < 0.001) fitting a third‐order polynomial regression model (R2 = 0.966; P = 0.008) (Fig. 4). A significant correlation was observed between FTM‐TRS scores and TEED1sec values during the follow‐up period (ρ = 0.927; P < 0.001).

Table 1.

Parameters for deep brain stimulation of the thalamic nucleus ventralis intermedius 6 months after surgery and at the last follow‐up

VIM‐DBS Parameters
6 Months Last Follow‐up
Patient Electrodes Stimulation Contacts V, v F, Hz P, μsec Stimulation Contacts V, v F, Hz P, μsec
1 Left Monopolar 2(−) 1.8 130 60 Monopolar 3(−) 3.1 130 60
Right Monopolar 6(−) 1.9 130 60 Monopolar 6(−) 2.8 140 90
2 Left Monopolar 0(−) 1.0 130 60 Monopolar 0(−) 1.5 130 60
3 Left Bipolar 2(−)3(+) 2.4 130 60 Bipolar 2(−)3(+) 3.7 130 90
Right Bipolar 6(−)5(+) 1.8 130 60 Bipolar 6(−)5(+) 3.7 130 90
4 Left Monopolar 0(−)1(−) 2.9 130 60 Bipolar 0(−)1(+) 3.7 140 120
Right Monopolar 4(−)5(−) 3.3 130 60 Bipolar 4(−)5(+) 3.6 140 60
5 Left Monopolar 1(−) 1.5 130 60 Monopolar 1(−) 2.4 130 60
Right Monopolar 5(−) 1.7 130 60 Monopolar 5(−) 3.2 130 60
6 Left Monopolar 5(−) 2.2 130 60 Bipolar 5(−)6(+) 3.2 140 90
7 Left Monopolar 1(−) 2.4 130 60 Bipolar 1(−)2(+) 2.8 140 90
Right Monopolar 5(−) 1.7 130 60 Monopolar 5(−) 2.8 140 60
8 Left Monopolar 1(−) 1.4 130 60 Bipolar 2(−)3(+) 3.8 140 60
Right Bipolar 7(−)4(+) 1.9 130 150 Bipolar 5(−)6(+) 4.2 130 90
9 Left Bipolar 0(−)1(+) 2.0 130 60 Monopolar 0(−)1(−) 3.7 145 90
10 Left Bipolar 0(−)1(+) 3.0 130 90 Monopolar 5(−) 3.7 145 90
Right Monopolar 4(−) 1.5 130 60 Bipolar 1(−)2(+) 4.1 145 90
11 Left Monopolar 1(−) 3.5 130 60 Monopolar 0(−) 3.5 130 90
Right Bipolar 3(−)1(+) 2.5 130 60 Bipolar 0(−)2(+) 3.7 130 90
12 Left Monopolar 0(−) 1.5 130 60 Monopolar 1(−) 2.9 130 60
Right Monopolar 6(−) 2.0 130 60 Monopolar 6(−) 3.4 130 60
13 Left Monopolar 2(−) 1.7 135 60 Monopolar 1(−) 3.9 145 90
Right Bipolar 0(−)1(+) 3.0 139 60 Bipolar 2(−)3(+) 3.2 160 90
14 Left Bipolar 0(−)1(+) 3.0 130 90 Bipolar 3(+)2(−)1(−) 3.8 145 120
Right Bipolar 0(−)1(+) 1.5 130 60 Bipolar 0(−)1(+) 2.0 130 60
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VIM‐DBS, deep brain stimulation of the thalamic nucleus ventralis intermedius; V, voltage; F, frequency; P, pulse width; (−), negative; (+), positive.

Figure 4.

Figure 4

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Progress of the total electrical energy delivered (TEED 1sec) and scores on the Fahn‐Tolosa‐Marin tremor rating scale (FTM‐TRS) during follow‐up are illustrated. The curve shows an initial exponential increase in TEED 1sec during the first 4 years followed by a plateau and a further increase from the seventh year after surgery onward (rl indicates regression line). A gradual worsening of FTM‐TRS scores began the first year after thalamic nucleus ventralis intermedius deep brain stimulation implantation. Results are presented as mean values ± standard deviation. Numbers in parentheses represent individual electrodes at each time interval.

Discussion

Our findings confirm that VIM‐DBS is an effective long‐term treatment for ET. However, although stimulation provided benefit throughout the follow‐up period (more than 10 years in some patients), we observed a slowly progressive worsening of ET scores over time, despite adjusting stimulation parameters to optimize tremor control. Several reasons have been proposed for the decline in the clinical efficacy of VIM‐DBS in ET, including tolerance,7, 8, 9 natural disease progression,10 suboptimal electrode placement,11 loss of the microthalamotomy effect,12 increased impedance in brain tissue over time,12, 13 and long‐term, stimulation‐induced effects.17

The loss of efficacy of VIM‐DBS over years cannot be explained by the “microthalamotomy effect,” which usually occurs over weeks to months.12 Suboptimal lead placement also seems to be an unlikely explanation in this study, because patients who had poor benefit after initial programming were excluded.

Despite extensive reprogramming of stimulation parameters, we detected a slow, declining benefit (as measured by the FTM‐TRS) that resembled the worsening in tremor scores over time observed in epidemiological studies on the natural progression of ET.3, 18 This suggests disease progression as a plausible cause for the partial loss of efficacy in tremor control over time. In 1 of those studies, the average annual increase in severity of ET from baseline ranged from 3.1% to 5.3%.3 The hypothesis of disease progression is also supported by the worsening of tremor scores in other small VIM‐DBS series with long‐term follow‐up.19, 20 In addition, findings from 2 studies of VIM‐DBS administered over a period of years showed that tremor scores when stimulation was turned off for 15 or 30 minutes were higher than the baseline scores (preimplantation).4, 5, 6, 7, 8, 9, 10 However, these observations should be interpreted with caution because of the short stimulation washout time and the possibility of a rebound effect.

As the disease progresses, some components of tremor, especially severe limb action tremor (which is usually more disabling than postural tremor in hand function and activities of daily living), may be more difficult to control using VIM‐DBS.19 With the progression of ET, the modulation of the synchronized oscillatory cerebellothalamocortical pathway induced by high‐frequency stimulation of the thalamic nucleus ventralis intermedius gradually loses effectiveness, perhaps because tremor may grow more dependent upon other pathophysiological factors that are not ameliorated by VIM‐DBS.

Tolerance to stimulation has also been considered a possible explanation for the gradual loss of efficacy of VIM‐DBS over time. Several investigators have reported the need to increase voltage, amplitude, or frequency during postoperative long‐term programming to maintain the clinical benefit of VIM‐DBS.7, 8, 17, 19, 20, 21, 22, 23, 24, 25 This observation is supported by the observation that stimulation holidays temporarily restored the efficacy of VIM‐DBS and that patients may benefit from intermittent use of the stimulator, usually turning it off during sleep.12, 23, 24, 25 Another study showed that the systematic optimization of VIM‐DBS parameters in ET led to a short‐term improvement, which habituated over time, suggesting that tolerance to stimulation could be improved using alternating stimulation protocols.10

We used TEED1sec—a measurement of the total electric energy delivered by the internal generator—to globally assess VIM‐DBS parameters. We found that TEED1sec increased exponentially over the first 4 years of VIM‐DBS to optimized tremor control, followed by a plateau of about 3 years, and a subsequent raise. This observation suggests that the development of tolerance to VIM‐DBS occurs during the first years of treatment, which may be related to the oscillatory nature of the cerebellothalamocortical circuit observed in this disease, with discharges of thalamic neurons coherent with the frequency of the peripheral tremor.26 High‐frequency thalamic stimulation could temporarily modulate this pathway, but subsequent habituation might occur through resetting of the thalamic oscillatory drive. Tolerance to DBS in other movement disorders has rarely been reported.

The increase in TEED1sec after 7 years of VIM‐DBS after a stable period of several years may be the consequence of increasing stimulation parameters to try to improve the progression of clinically disabling tremor. Gliosis around the placement of the electrodes,13, 27, 28, 29, 30 although it cannot be completely ruled out, seems an unlikely cause for the late decline of VIM‐DBS efficacy in this study.

In conclusion, our findings suggest that the waning effect of VIM‐DBS over time in patients with ET may be the consequence of a combination of factors. Superimposed on the progression of the disease, which is present throughout the follow‐up period, tolerance may occur during the early years of stimulation. Nevertheless, despite these considerations, VIM‐DBS remains an effective long‐term treatment for severe, otherwise untreatable ET. New developments in stimulation devices and a better understanding of tremor pathophysiology should improve the efficacy of VIM‐DBS in ET.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

P.M.R.C.: 1A, 1B, 3A

A.V.: 1A, 1B, 3A

C.F.C: 1C, 3B

J.G.: 1C; 3B

B.D.L.C.‐F.: 1A, 3B

F.G.: 1A, 3B

Disclosures

Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the previous 12 months: Francisco Grandas has received honoraria from AbbVie for Advisory Board participation and a research grant from UCB. The remaining authors declare that there are no conflicts of interest relevant to this work.

Acknowledgements

We thank Jose María Bellón for his review of the statistical analysis presented in this article.

Relevant disclosures and conflicts of interest are listed at the end of this article.

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